Final Report Summary - BIOCCORA (Full biomechanical characterization of the coronary atherosclerotic plaque: biomechanics meets imaging)
Coronary atherosclerotic plaque rupture is the main cause of myocardial infarction, which is a life threatening event. Biomechanical parameters, such as the blood flow induced shear stress and stress in the wall, play an essential role in both the initiation/ generation and rupture of atherosclerotic plaques. In this project new technology was developed to assess both shear stress and wall stress in coronary arteries. A conventional method to assess shear stress in coronary arteries is computational modeling using a 3D reconstruction of the coronary artery. Since at that time, the 3D reconstruction methodology did not include side branches and the vessel wall composition, we had to go beyond the state of the art. Therefore a new 3D reconstruction methodology for coronary arteries was developed using fusion of CT and multiple invasive imaging modalities. This approach allowed us to include bifurcations in the geometry what made the shear stress assessment more reliable and at the other hand to have a detailed description of the plaque composition. Based on the local plaque composition, a novel approach was published that for the first time demonstrated the feasibility of local wall stress analysis in human coronary arteries in living patients. Based on earlier studies, we hypothesized that shear stress has a long term influence on plaque progression and destabilization and that the local wall stress points to current risk at plaque rupture. My study aided in testing this hypothesis by using longitudinal imaging studies in atherosclerotic animals and patients with coronary artery disease. Furthermore, we set out to test the influence of the multi-directionality of blood flow, and thus of wall shear stress, on plaque composition changes over time. Multi-directionality of blood flow is a direct consequence of the pulsatile nature of the blood, but was never considered in studies on shear stress related plaque progression before. Therefore, five metrics that describe (multidirectional) wall shear stress were assessed and related to local plaque growth and plaque composition.
For our studies we used adult pigs with a genetic defect (familial hypercholesterolemia) to create a more human-like model of atherosclerosis. Upon feeding a high fat diet, the pigs developed mild to severe plaques over a period of 12 months. To elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein profiling was performed. We monitored plaque progression and composition at 3, 9 and 9-12 months using serial (invasive) imaging and histology. The newly developed 3D-reconstruction methodology of the arterial lumen, in combination with local flow velocity measurements, was used to calculate wall shear stress. Local plaque progression and composition changes were linked to the local shear stress (5 multi-directional shear stress parameters). A very new finding was that the pigs showed marked differences between mildly-diseased pigs which exclusively developed early lesions (n=5) and advanced-diseased pigs which developed human-like, lumen intruding plaques (n=5) with large necrotic cores, intra-plaque hemorrhage and calcifications. However, no differences in conventional risk factors were observed between the mildly and advanced diseased pigs. We found a distinct lipid profile in the advanced diseased pigs compared to the mildly diseased pigs. A similar lipid profile was observed in patients with a similar genetic defect as the pigs. In both groups of pigs with advanced and mild disease, low time-averaged WSS and high multidirectional WSS resulted in the highest plaque growth rate, both in plaque initiation and progression. A similar relation was found between baseline wall shear stress and vulnerable plaque components. Four out of five multidirectional shear stress metrics had good predictive values for the development of and for advanced fibrous cap atheroma development
Conclusions – This study demonstrated that this animal model develops plaques with a wide range in severity and complexity of atherosclerotic plaque composition. Henceforth this new animal model was used for studies on shear stress related plaque progression, but can also be used to investigate new invasive treatment strategies and imaging of adverse plaque components. Moreover a specific lipid profile was linked to disease severity. This new lipid profile has high potential to aid in identifying patients that are at increased of developing major cardiovascular events. Further studies should prove its applicability. Furthermore, low and multidirectional WSS promote both initiation and progression of coronary atherosclerotic plaques. The high predictive values of the multidirectional WSS metrics indicate their potential as an additional clinical marker for vulnerable disease.
49 patients were enrolled in a patient study, who were treated for a local lumen obstruction, according to local treatment standards and subsequently, at least one, non-treated, coronary segment was serially imaged using multiple imaging modalities. In 41 patients invasive imaging was repeated at one year follow up. Written informed consent was obtained from all patients. In a first study, we investigated the possible synergistic effect of local lipid levels (as detected by near-infrared spectroscopy (NIRS)) and systemic lipid levels on shear stress related atherosclerotic plaque progression. Patients with high levels of lipids demonstrated a trend to higher plaque growth in low shear stress regions and high multidirectional shear stress parameters. Regions presenting with lipid rich plaque showed more plaque progression when colocalized with high multi-directonal shear stress and more plaque regression in regions additionally exposed to high shear stress compared to regions without lipids. Conclusion – This study showed that lipid-rich plaques, as assessed by (NIRS) and local shear stresses act synergistically in plaque progression or regression in human coronary arteries. This finding suggests that combining local WSS information with knowledge on local plaque composition could improve patient risk assessment
Patients are often treated for atherosclerostic plaque build up close to side branches with stent implantation. Stents are implanted to prevent the lumen from passive recoil. However, the final stent geometry is not always optimal. Our new 3D reconstruction methodology, which includes the side branches and wall composition, would allow for planning of such a stenting treatment. Therefore as a first step, computer simulations of stent implantation were performed in bifurcation models with the most severe pattern of lumen narrowing having a significant stenosis in mother and both daughter branches. The stenting procedure, as is performed in patients in the cath-lab, was replicated including post-dilation after main branch stenting. Two bifurcation angles (45°, 70°) and four plaque types (fully lipid, fully fibrous, lipid with half and fully calcified ring distal to the carina) were tested. Two post-dilation balloons of different lengths (15 mm and 9 mm) were also investigated. Our data showed that stenting in this bifurcation region caused an ovalisation of the side branch ostium that might appear as a significant stenosis on two-dimensional angiography. Plaque type had a higher impact than bifurcation angle on sidebranch ostium shape. A shorter balloon (9 mm) for proximal optimisation reduced side branch lumen volume compromise.
This project for the first time allowed for extensive research on the role of biomechanical parameters on the initiation and progression of atherosclerotic plaques. The new data hold promise for application in the clinic to identify patients at risk for cardiovascular events.
For our studies we used adult pigs with a genetic defect (familial hypercholesterolemia) to create a more human-like model of atherosclerosis. Upon feeding a high fat diet, the pigs developed mild to severe plaques over a period of 12 months. To elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein profiling was performed. We monitored plaque progression and composition at 3, 9 and 9-12 months using serial (invasive) imaging and histology. The newly developed 3D-reconstruction methodology of the arterial lumen, in combination with local flow velocity measurements, was used to calculate wall shear stress. Local plaque progression and composition changes were linked to the local shear stress (5 multi-directional shear stress parameters). A very new finding was that the pigs showed marked differences between mildly-diseased pigs which exclusively developed early lesions (n=5) and advanced-diseased pigs which developed human-like, lumen intruding plaques (n=5) with large necrotic cores, intra-plaque hemorrhage and calcifications. However, no differences in conventional risk factors were observed between the mildly and advanced diseased pigs. We found a distinct lipid profile in the advanced diseased pigs compared to the mildly diseased pigs. A similar lipid profile was observed in patients with a similar genetic defect as the pigs. In both groups of pigs with advanced and mild disease, low time-averaged WSS and high multidirectional WSS resulted in the highest plaque growth rate, both in plaque initiation and progression. A similar relation was found between baseline wall shear stress and vulnerable plaque components. Four out of five multidirectional shear stress metrics had good predictive values for the development of and for advanced fibrous cap atheroma development
Conclusions – This study demonstrated that this animal model develops plaques with a wide range in severity and complexity of atherosclerotic plaque composition. Henceforth this new animal model was used for studies on shear stress related plaque progression, but can also be used to investigate new invasive treatment strategies and imaging of adverse plaque components. Moreover a specific lipid profile was linked to disease severity. This new lipid profile has high potential to aid in identifying patients that are at increased of developing major cardiovascular events. Further studies should prove its applicability. Furthermore, low and multidirectional WSS promote both initiation and progression of coronary atherosclerotic plaques. The high predictive values of the multidirectional WSS metrics indicate their potential as an additional clinical marker for vulnerable disease.
49 patients were enrolled in a patient study, who were treated for a local lumen obstruction, according to local treatment standards and subsequently, at least one, non-treated, coronary segment was serially imaged using multiple imaging modalities. In 41 patients invasive imaging was repeated at one year follow up. Written informed consent was obtained from all patients. In a first study, we investigated the possible synergistic effect of local lipid levels (as detected by near-infrared spectroscopy (NIRS)) and systemic lipid levels on shear stress related atherosclerotic plaque progression. Patients with high levels of lipids demonstrated a trend to higher plaque growth in low shear stress regions and high multidirectional shear stress parameters. Regions presenting with lipid rich plaque showed more plaque progression when colocalized with high multi-directonal shear stress and more plaque regression in regions additionally exposed to high shear stress compared to regions without lipids. Conclusion – This study showed that lipid-rich plaques, as assessed by (NIRS) and local shear stresses act synergistically in plaque progression or regression in human coronary arteries. This finding suggests that combining local WSS information with knowledge on local plaque composition could improve patient risk assessment
Patients are often treated for atherosclerostic plaque build up close to side branches with stent implantation. Stents are implanted to prevent the lumen from passive recoil. However, the final stent geometry is not always optimal. Our new 3D reconstruction methodology, which includes the side branches and wall composition, would allow for planning of such a stenting treatment. Therefore as a first step, computer simulations of stent implantation were performed in bifurcation models with the most severe pattern of lumen narrowing having a significant stenosis in mother and both daughter branches. The stenting procedure, as is performed in patients in the cath-lab, was replicated including post-dilation after main branch stenting. Two bifurcation angles (45°, 70°) and four plaque types (fully lipid, fully fibrous, lipid with half and fully calcified ring distal to the carina) were tested. Two post-dilation balloons of different lengths (15 mm and 9 mm) were also investigated. Our data showed that stenting in this bifurcation region caused an ovalisation of the side branch ostium that might appear as a significant stenosis on two-dimensional angiography. Plaque type had a higher impact than bifurcation angle on sidebranch ostium shape. A shorter balloon (9 mm) for proximal optimisation reduced side branch lumen volume compromise.
This project for the first time allowed for extensive research on the role of biomechanical parameters on the initiation and progression of atherosclerotic plaques. The new data hold promise for application in the clinic to identify patients at risk for cardiovascular events.